CD4 cell counts have been shown to initially increase sharply in response to the initiation of effective antiretroviral therapy (ART). This initial increse is then followed by an attenuated rate of increase. However, many questions remain regarding how CD4 levels respond to ART. CD4 response to ART has been analyzed by examining the median CD4 cell count over time since the initiation of treatment, linear mixed models, or generalized linear models. These approaches provide the general CD4 response pattern in the study sample. Yet other patterns, more complex patterns in individual response are likely to be present within a population initiating ART. We hypothesize that an individual's response pattern may cluster within several distinct response pattern types such as effective responders (quickly increase in CD4 which plateaus at normal CD4 levels), ineffective responders (slowly increase in CD4 and plateaus below normal), non-responders (CD4 is stable or very slowly increases), intermittent responders (individuals who respond but then decrease), as well as other potential response patterns. Additionally, the question of whether CD4 levels after the initiation of effective treatment plateau at normal or below normal levels remains unanswered. These gaps in knowledge hinder the development of a definition of successful immune response as current HIV guidelines only give broad guidance. These guidelines state that the goal of treatment is to restore and preserve immunologic function but do not outline a specific objective in terms of achieving an obtainable CD4 count. Therefore the goal of the Global immunological Response to Effective Antiretroviral Therapy: CD4 (GiREAT:CD4) is to 1) identify typical CD4 patterns of response to ART and identify potential predictors of these patterns including a web-based tool for predicting future CD4 response; 2) Develop CD4 response charts which are analogous to children's growth charts as a tool for providers and identify the rate of attenuation of CD4 increase and the level of CD4 plateau; and 3) determine the association of CD4 response patterns and individual's response with all-cause and cause-specific mortality. These differences in CD4 response to ART will be examined across 7 global regions to determine if regional differences in response are present. GiREAT:CD4 will be nested within the International epidemiologic Database to Evaluate AIDS (IeDEA) an international research consortium of seven regional centers established by the National Institute of Allergy and Infectious Disease. GiREAT:CD4 takes an innovative fresh approach to examining the question of how CD4 levels respond to the initiation of ART. This will be achieved using novel analytical methods as well as through the development of new statistical methods. The information gleaned through GiREAT:CD4 will define a successful immune response to ART and thereby improve clinical care of HIV infected individuals.